Chromosome 9p21 Research Articles

Intramural and Adapted-Germ Cell Neoplasia In situ

Germ cell neoplasia in situ emerges as a precursor lesion configuring type II germ cell tumours as testicular seminoma or post-pubertal non-seminomatous testicular germ cell tumours. Lesion is comprised of neoplastic gonocyte-like cells, latent totipotent or naive germ cells with developmental potential situated within ‘spermatogonial niche’ of seminiferous tubules. Germ cell neoplasia in situ delineates an increased incidence with conditions as uncorrected cryptorchidism, ambiguous genitalia, infertility or preceding history of post-pubertal germ cell tumour within contralateral testis. Neoplasm demonstrates aneuploidy or polypoid genotype with additional chromosomal gains as is chromosome 12p upon commencement of neoplastic invasion. Neoplastic cells appear enlarged, atypical, gonocyte-like and are incorporated with abundant, clear cytoplasm, enlarged, hyper chromatic nuclei, coarse nuclear chromatin, angulated cellular margins and prominent nucleoli.

Huddled and Preternatural- Atypical Lobular Hyperplasia

Atypical lobular hyperplasia manifests as a clonal proliferation of dis-cohesive epithelial cells emerging from terminal duct lobular units. Neoplasm appears reminiscent of lobular carcinoma in situ (LCIS) although cellular quantification is reduced. Characteristically, the incidentally discovered lesion is associated with dysfunction or decimation of E-cadherin. Additionally designated as lobular intraepithelial neoplastic 1 (LIN1), tumefaction exemplifies a female preponderance. Typically, adult subjects are implicated. Tumefaction is commonly encountered within the fifth decade although no age of disease emergence is exempt. Atypical lobular hyperplasia is detected within<1% of core needle biopsies adopted for evaluating BI-RADS 4 lesions [1,2]. Atypical lobular hyperplasia may incriminate bilateral breasts wherein specific lesion localization is absent. Tumefaction exhibits loss of chromosome 16qand deletion of CDH1 genes with loss of function of E-cadherin, a Tran’s membrane cell adhesion molecule. Alternatively, altered function of E-cadherin may occur. Exceptionally, various adhesion proteins are implicated wherein E-cadherin molecule appears stable [1,2]. Characteristically, atypical lobular hyperplasia is a diploid neoplasm. Tumefaction exhibits loss of heterozygosis (LOH) at chromosome 16q. A subset of neoplasms demonstrates methylation of CDH1 gene. Several tumefaction express loss of chromosome 22q and 16p, gain of chromosome 2p11.2, 5q32- 33.1 (CSF1R), 6q, 11q13 or 14q32.33.

Molecular Profile of the HepG2 Tumor Cell Line

Cell lines are widely used in scientific research due to their accessibility, stability, and functional similarity to the original cells. The HepG2 line, being the fourth most popular cell culture, is often used in toxicological and metabolic studies due to its partial retention of hepatocyte properties.In our study, the molecular portrait of the HepG2 cell culture was constructed for the first time. To build this portrait, we used previously obtained data for a single sample, including results of whole-genome sequencing (WGS), whole-genome bisulfite sequencing (WGBS), transcriptome (RNA-seq), translatome (Polysome-seq), and proteome (LC-MS/MS) profiling. For the assessment of HepG2 cell line heterogeneity, we analyzed whole-genome and transcriptome data published in the NCBI SRA database, as well as proteome research results available in the PRIDE resource.Our study showed that the HepG2 cell line generally demonstrates a high degree of stability at the genomic and transcriptomic levels; however, samples from China require closer attention when transferring the results of transcriptomic and proteomic experiments. The HepG2 genotype is characterized by stable chromosomal rearrangements, such as translocation between the short arms of chromosomes 1p and 21p, tetrasomy of chromosome 20, loss of the short arm of all SAT chromosomes, and the long arm of the Y chromosome. Despite the absence of 1216 protein-coding genes at the genomic level, 12,602 genes are expressed at the transcriptomic level, of which only 10,461 are detected at the translatome level, and only 1027 genes are identified at the proteome level, which is related to the limitations of mass spectrometry sensitivity. As a result of the omics data analysis, we presented a detailed molecular portrait of the HepG2 cell culture, illustrating the omics profile at various levels for each gene.

A Comprehensive Review of Chromosome 7, Partial Monosomy 7p Syndrome

Partial monosomy syndrome of chromosome 7p is a rare chromosomal disorder characterized by the deletion (monosomy) of part of the short arm (p) of chromosome number 7 (7p). Associated symptoms and findings may be variable and may depend on the size and specific location of the 7p deleted segment. However, in many cases, there is premature closure of the fibrous joints (cranial sutures) between some of the bones of the skull (craniosynostosis), leading to an abnormal head shape. For example, depending on the specific sutures involved, the forehead may appear unusually “triangular” (trigonocephaly) or the head may appear abnormally long and narrow with a pointed or conical point (toriscephaly). Partial monosomy syndrome of chromosome 7p is also usually characterized by premature closure of one or more fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis), potentially leading to a deformed skull and abnormal head shape. In people with partial monosomy syndrome of chromosome 7p, there is a deletion (monosomy) of part of the short arm (p) of chromosome number 7. Based on reports in the medical literature, there is considerable variability in the size and location of the 7p deleted segment, potentially affecting the range and severity of symptoms and associated findings. Reported cases include variable “distal” deletions that extend to the terminal band (eg, from 7p13-pter to 7p21,p22-pter) and various “interstitial” deletions (eg, from 7p13 or 7p15 to 7p21).

Genetic Characterization of Pediatric Mixed Phenotype Acute Leukemia (MPAL).

Mixed phenotype acute leukemia (MPAL) is a rare hematologic malignancy in which the leukemic cells cannot be assigned to any specific lineage. The lack of well-defined, pathogenetically relevant diagnostic criteria makes the clinical handling of MPAL patients challenging. We herein report the genetic findings in bone marrow cells from two pediatric MPAL patients. Bone marrow cells were examined using G-banding, array comparative genomic hybridization, RNA sequencing, reverse transcription polymerase chain reaction, Sanger sequencing, and fluorescence in situ hybridization. In the first patient, the genetic analyses revealed structural aberrations of chromosomal bands 8p11, 10p11, 11q21, and 17p11, the chimeras MLLT10::PICALM and PICALM::MLLT10, and imbalances (gains/losses) on chromosomes 2, 4, 8, 13, and 21. A submicroscopic deletion in 21q was also found including the RUNX1 locus. In the second patient, there were structural aberrations of chromosome bands 1p32, 8p11, 12p13, 20p13, and 20q11, the chimeras ETV6::LEXM and NCOA6::ETV6, and imbalances on chromosomes 2, 8, 11, 12, 16, 19, X, and Y. The leukemic cells from both MPAL patients carried chromosome aberrations resulting in fusion genes as well as genomic imbalances resulting in gain and losses of many gene loci. The detected fusion genes probably represent the main leukemogenic events, although the gains and losses are also likely to play a role in leukemogenesis.

Multiple sclerosis-associated uveitis - A series from South India.

To report clinical profiles of multiple sclerosis (MS)-associated uveitis in seven cases from a single tertiary eye care center in South India. Retrospective case series 2013-2023. Seven cases of MS-associated uveitis were retrieved from our databases. There were five females and two males. The diagnosis of MS was made by the neurologist in all cases. Bilaterality was seen in all cases. Intermediate uveitis was the most common presentation (five cases). It was associated with peripheral retinal vasculitis (two cases) and disc pallor (two cases). Fuchs heterochromic iridocyclitis (one case) and incomplete Vogt-Koyanagi-Harada (VKH)-like presentation with a peripapillary choroidal neovascular membrane (one case) were the other presentations. In the case with incomplete VKH-like presentation, whole genome sequencing revealed a heterozygous non-synonymous variation (c.1228C>T) in exon 10 of TNFRSF1A, suggestive of susceptibility to multiple sclerosis 5 due to mutation in the TNFRS1A gene on chromosome 12p13.31. All cases received systemic steroids. Azathioprine (three cases) and rituximab (three cases) were the commonly used immunomodulatory drugs. The visual outcome was good in all cases at the last follow-up. MS-associated uveitis is underreported in India. This series highlights the clinical profile of MS-associated uveitis in India.

Cancer predisposition signaling in Beckwith-Wiedemann Syndrome drives Wilms tumor development.

Wilms tumor (WT) exhibits structural and epigenetic changes at chromosome 11p15, which also cause Beckwith-Wiedemann Syndrome (BWS). Children diagnosed with BWS have increased risk for WT. The aim of this study is to identify the molecular signaling signatures in BWS driving these tumors. We performed whole exome sequencing, methylation array analysis, and gene expression analysis on BWS-WT samples. Our data were compared to publicly available nonBWS data. We categorized WT from BWS and nonBWS patients by assessment of 11p15 methylation status and defined 5 groups- control kidney, BWS-nontumor kidney, BWS-WT, normal-11p15 nonBWS-WT, altered-11p15 nonBWS-WT. BWS-WT samples showed single nucleotide variants in BCORL1, ASXL1, ATM and AXL but absence of recurrent gene mutations associated with sporadic WT. We defined a narrow methylation range stratifying nonBWS-WT samples. BWS-WT and altered-11p15 nonBWS-WT showed enrichment of common and unique molecular signatures based on global differential methylation and gene expression analysis. CTNNB1 overexpression and broad range of interactions were seen in the BWS-WT interactome study. While WT predisposition in BWS is well-established, as are 11p15 alterations in nonBWS-WT, this study focused on stratifying tumor genomics by 11p15 status. Further investigation of our findings may identify novel therapeutic targets in WT oncogenesis.

Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer.

Large-scale chromosomal aberrations are prevalent in human cancer, but their function remains poorly understood. We established chromosome-engineered hepatocellular carcinoma cell lines using CRISPR-Cas9 genome editing. A 33-mega-base pair region on chromosome 8p (chr8p) was heterozygously deleted, mimicking a frequently observed chromosomal deletion. Using this isogenic model system, we delineated the functional consequences of chr8p loss and its impact on metastatic behavior and patient survival. We found that metastasis-associated genes on chr8p act in concert to induce an aggressive and invasive phenotype characteristic for chr8p-deleted tumors. Genome-wide CRISPR-Cas9 viability screening in isogenic chr8p-deleted cells served as a powerful tool to find previously unidentified synthetic lethal targets and vulnerabilities accompanying patient-specific chromosomal alterations. Using this target identification strategy, we showed that chr8p deletion sensitizes tumor cells to targeting of the reactive oxygen sanitizing enzyme Nudix hydrolase 17. Thus, chromosomal engineering allowed for the identification of novel synthetic lethalities specific to chr8p loss of heterozygosity.

The Role of Innovation Technology in the Rehabilitation of Patients Affected by Huntington's Disease: A Scoping Review.

Huntington's disease is an autosomal dominant neurodegenerative disease caused by the repetition of cytosine, adenine, and guanine trinucleotides on the short arm of chromosome 4p16.3 within the Huntingtin gene. In this study, we aim to examine and map the existing evidence on the use of innovations in the rehabilitation of Huntington's disease. A scoping review was conducted on innovative rehabilitative treatments performed on patients with Huntington's disease. A search was performed on PubMed, Embase, Web of Science, and Cochrane databases to screen references of included studies and review articles for additional citations. Of an initial 1117 articles, only 20 met the search criteria. These findings showed that available evidence is still limited and that studies generally had small sample sizes and a high risk of bias. Regarding cognitive rehabilitation, it has emerged that VR- and PC-based methods as well as NIBS techniques are feasible and may have promising effects in individuals with Huntington's disease. On the other hand, scarce evidence was found for cognitive and motor training that might have a slight impact on overall cognitive function in individuals with Huntington's disease. Data show that further investigation is needed to explore the effects of innovative rehabilitation tools on cognition, especially considering that cognitive and psychiatric symptoms can precede the onset of motor symptoms by many years.

Wolf-hirschhorn Syndrome in Malaysia

Introduction: Wolf–Hirschhorn syndrome (WHS) is rare but a well-known clinical condition due to partial deletion of the short arm of chromosome 4 (4p). It is distinguished by a distinctive facial appearance known as the “Greek warrior helmet”, impaired growth and development, intellectual incapacity and seizures. The features of WHS vary between individuals based on the size and location of the missing piece of chromosome 4. Methods: Six cases of unsuspected WHS were diagnosed from 2011 to 2020 using conventional cytogenetic and fluorescent in situ hybridization (FISH) with a WHS probe. Result: Four of them had a visible cytogenetic deletion on chromosome 4p whereas the remaining two were evaluated with fluorescent in situ hybridization (FISH) using a WHS probe. Conclusion: Conventional cytogenetic testing may yield normal findings and it does not rule out the syndrome. Targeted FISH with a WHS probe is a better option.

Bioinformatics Analysis of Disc Large Homolog-4 (DLG-4) As Parameters in Neuroplasticity

Disc Large Homolog-4 (DLG-4), also known as Post Synaptic Density 95 (PSD95) is believed to have an important role in the function and organization of the synapse. DLG-4 is the main protein structure at the synapse that is able to bind to various molecules on the surface of the postsynaptic membrane. This review aims to determine the biomolecular characteristics of DLG-4 and the role of DLG-4 as an important parameter in neuroplasticity. Biomolecular characteristic analysis was obtained through various bioinformatics websites namely NCBI, PROTPARAM, TMHMM, PEPTIDE CUTTER, NETNGLYC, TARGETP and KEGG PATHWAY. The DLG-4 gene is located on chromosome 17p13.1 and has 25 exon. The DLG-4 protein consists of 764 amino acids with a molecular weight of 80.47 kDa. DLG-4 has a structure of 3 N-terminal PDZ domains, a Src Homology 3 (SH3) domain and a guanilate kinase-like C-terminal domain. This protein has a stability score of 48.61. The aliphatic index is 85.42. DLG-4 is found inside, outside, and on transmembranes, as determined by THMM. There are 37 enzymes that are predicted to be able to split the DLG-4 protein. The DLG-4 protein shows 3 potential sites of glycosylation of amino acids. The target location of the DLG-4 protein is mostly in other locations (other = 0.6556), secretory pathway (0.3328), and only slightly in mitochondria (0.0116). The DLG-4 protein is strongly associated with the glutamatergic system in postsynaptic neurons. The glutamatergic system is concerned with the molecular mechanism of memory development and cognitive function, long-term potentiation (LTP). These findings support the fact that DLG-4 protein plays a role in neuroplasticity mechanisms in the brain.

Schnyders corneal dystrophy: A case report

Schnyder corneal dystrophy (SCD) is a rare, autosomal dominant inherited dystrophy affecting the anterior stroma of the cornea. It is caused by a local metabolic defect mapped on the UBIAD1 gene chromosome 1p36. It is known to causes progressive bilateral opacification of the cornea due to an abnormal accumulation of phospholipids and cholesterol in the cornea. In our case a 22-year-old male with vision loss and ocular discomfort revelled multiple grey, infiltrates or disc like opacities in both eyes arranged in circinate manner on slit-lamp, involving the sub-epithelium and stroma. On anterior segment OCT, involvement of the entire stroma was noted with Increased deposits seen in the anterior 1/3rd of the stroma. Central corneal thickness was also increased in the areas of depositions, while systemic evaluation showed dyslipidemia. Clinical as well as anterior segment OCT findings suggest of intrastromal deposits in a ring like pattern, suggestive of schnyders corneal dystrophy. AS-OCT is vital in such cases to help differentiate epithelial involvement from stromal, thus altering the therapeutic approach. Patients can be planned for penetrating keratoplasty if visual acquits is affected.

Targeting P53 Gene in Breast Cancer

Infectious diseases and breast cancer rely heavily on p53, a tumor suppressor that protects genetic integrity. It is present on chromosome 17p13 and controls angiogenesis, programmed cell death, and cell proliferation. The expression of p53 and its isoforms is more predictive of treatment outcomes and responses to chemotherapy for breast cancer patients than the presence or absence of TP53 mutations. Subtype-dependent mutations of p53's negative regulator MDM2 can both be signs of p53 deactivation in breast cancer. Targeting both wild-type and p53 mutant across various subtypes of breast cancer is one possible treatment strategy. Notably, through paracrine signaling, mutant p53 in stromal fibroblasts speeds up the formation of breast tumors. In the progression and trajectory of breast cancer, the pivotal involvement of the p53 gene, alongside the bcl-2 proto-oncogene, is noteworthy. Addressing the role of p53 is crucial in the context of breast cancer development and its course.

Network targeting combination therapy of synthetic lethal vulnerabilities in 9p21-deficient glioblastoma: A case report.

Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships, which create the possibility of targeting vulnerabilities arising from the loss of tumor suppressor genes. For synthetic lethal vulnerabilities that are not present in normal tissues, lethal cytotoxicity against cancer cells can be achieved without the necessity of causing normal tissue toxicity. This case report describes a patient with progressive glioblastoma with homozygous deletion of chromosome 9p21. Vulnerabilities created by CDKN2A and MTAP loss were exploited with pemetrexed, bevacizumab, and candesartan to achieve a clinically meaningful remission by targeting multiple synthetic lethal nodes. Synthetic lethality can reveal the basis for exceptional responsiveness, thus extending the utility of molecular profiling and fulfilling the promise of precision medicine.

High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis.

The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods. We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls. We identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk. The results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

Renal Inflammatory Myofibroblastic Tumor in an Infant: Case Report with Review of Literature

AbstractInflammatory myofibroblastic tumor (IMT) is an intermediate-grade neoplasm of myofibroblastic lineage occurring due to a cytogenetic clonal abnormality of chromosome 2p23. Pediatric renal IMTs are rare and infant renal IMTs are almost anecdotal. We herein report a 1-year-old female child who presented with a firm mass in the right lumbar region. Biopsy, and later, surgical resection revealed a tumor composed of spindle cells with intermixed plasma cells. On immunohistochemistry (IHC), the lesional cells were positive for smooth muscle actin and anaplastic lymphoma kinase (ALK). A diagnosis of IMT was made based on morphology and IHC. Diagnosis of renal IMTs become challenging especially in a tiny biopsy wherein clear cell sarcoma of kidney, Wilms tumor with predominant mesenchymal component, congenital mesoblastic nephroma, and metanephric stromal tumor are the differential diagnoses in this age group. Renal IMTs generally have better prognosis as compared to extrarenal IMTs. Approximately, 50 to 60% of these tumors harbor ALK gene rearrangement as demonstrated by positivity for ALK IHC. ALK inhibitors like crizotinib or ceritinib can be given for advanced metastatic tumors.

Abstract C135: Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers

Abstract Homozygous deletions of the p16/CDKN2a (cyclin dependent kinase inhibitor 2A) locus, which is responsible for regulating the cell cycle, are commonly found in cancer and often involve the deletion of adjacent genes. One such adjacent gene is methylthioadenosine phosphorylase (MTAP), involved in metabolism, located on chromosome 9p21 in close proximity to the p16/CDKN2A tumor-suppressor locus. Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme, competing with the substrate S-adenosylmethionine (SAM) required for methylation reactions. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced. This heightened sensitivity to modulation of methylosome activity makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Hence, selective targeting of PRMT5 in cancers with homozygous MTAP deletion represents a promising strategy for specifically eliminating cancer cells with this genetic alteration. Ryvu is developing two independent series of PRMT5 inhibitors characterized by good drug-like physicochemical properties and inhibition of methyltransferase activity with IC50 values in the low nanomolar range. Structure-based lead optimization enabled rapid expansion and delivery of a compound library with novel intellectual property (IP), high target engagement in cells and selective potency in MTAP-deleted cell lines. In long-term three-dimensional (3D) cell culture, Ryvu compounds selectively inhibit the growth of MTAP-deficient cancer cells, which correlate strongly with the inhibition of PRMT5-dependent symmetric protein dimethylation (SDMA) in these cells. The synthesized library allowed the identification of compounds with more than 350-fold selectivity between the effects observed in MTAP-deficient and WT cells for both SDMA and growth inhibition. The DMPK profile of these compounds allows for oral administration, which enables testing of antitumor activity in MTAP null tumor xenograft bearing mice. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies provide a rationale for the further development of our chemical series of MTA cooperative PRMT5 inhibitors toward a clinical candidate. Citation Format: Adam Radzimierski, Aneta Bobowska, Agata Stachowicz, Kamil Kus, Kamila Kozłowska-Tomczyk, Agnieszka Ludwig-Słomczyńska, Aniela Gołas, Paulina Podkalicka, Andrzej Gondela, Nicolas Boutard, Grzegorz Ćwiertnia, Krzysztof Brzózka, Anna Bartosik, Mateusz Nowak, Didier Pez. Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C135.

PSP/DEGESCO: A Progressive Supranuclear Palsy Genome‐Wide Association Study in the Spanish Population

AbstractBackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy. We genotyped all the available histopatologically confirmed PSP cases from the Spanish National Biobank Network and patients with a probable PSP diagnosis recruited from research groups linked to the Dementia Genetics Spanish Consortium (DEGESCO). Here, we present the results of the genome‐wide association study (GWAS) performed after the first stage of this project.MethodDNA samples were genotyped by the Centro Nacional de Genotipado (Santiago de Compostela, Spain) using the Affymetrix Axiom 815K Spanish biobank array. After quality control, we kept 156 histopathological (discovery) and 197 clinical (validation) PSP samples. Then, we selected 650 and 800 sex‐matched controls from GR@ACE/DEGESCO for stratified genome‐wide association of the discovery and validation sets, respectively (Table 1). We ran PC1‐4 adjusted logistic regressions with plink v2.00 and meta‐analyzed the discovery and validation sets using METAL. Finally, we meta‐analyzed our results with 36 previously reported SNPs1 reaching the largest PSP sample size to date (N = 3053).ResultWe found a strong genome‐wide significant (GWS) signal associated to the MAPT H1/H2 haplotype (rs8070723 G: OR = 3.40; 95%CI = 2.64‐4.39; p = 2.60·10−20, Figure 1) and identified a previously unreported signal in chromosome 7p13 (rs76827509 T: OR = 0.45; 95%CI = 0.35‐0.58; p = 3.09·10−10). We replicated, with nominal significance, 5 GWS SNPs reported in previous GWAS (Table 2) and found significant effects for NFASC and TOMM40. Because APOE and TOMM40 are in strong linkage disequilibrium, we also checked the effect of APOE variants. We found a protective effect (OR = 0.66; 95%CI = 0.48‐0.90; p = 9.75·10−3) of the rs429358 C allele (APOE ε4) in our dataset.ConclusionThe strong GWS signal of the H1 haplotype confirms the validity of our GWAS results2. We were able to replicate several PSP loci (Table 1). The NFASC variant reached borderline GWS significance after meta‐analysis and is a good PSP risk factor candidate. Finally, the APOE ε4 allele was protective for PSP in our cohort. The second stage of PSP/DEGESCO genotyped 218 additional PSP samples. 1 Sanchez‐Contreras, M. Y. et al. Mol. Neurodegener. (2018) 2 Höglinger, G. U. et al. in Nature Genetics (2011)

Clinical and genomic differences in supratentorial versus infratentorial NF2 mutant meningiomas.

Mutations in NF2 are the most common somatic driver mutation in sporadic meningiomas. NF2 mutant meningiomas preferentially arise along the cerebral convexities-however, they can also be found in the posterior fossa. The authors investigated whether NF2 mutant meningiomas differ in clinical and genomic features based on their location relative to the tentorium. Clinical and whole exome sequencing (WES) data for patients who underwent resection of sporadic NF2 mutant meningiomas were reviewed and analyzed. A total of 191 NF2 mutant meningiomas were included (165 supratentorial, 26 infratentorial). Supratentorial NF2 mutant meningiomas were significantly associated with edema (64.0% vs 28.0%, p < 0.001); higher grade-i.e., WHO grade II or III (41.8% vs 3.9%, p < 0.001); elevated Ki-67 (55.0% vs 13.6%, p < 0.001); and larger volume (mean 45.5 cm3 vs 14.9 cm3, p < 0.001). Furthermore, supratentorial tumors were more likely to harbor the higher-risk feature of chromosome 1p deletion (p = 0.038) and had a larger fraction of the genome altered with loss of heterozygosity (p < 0.001). Infratentorial meningiomas were more likely to undergo subtotal resection than supratentorial tumors (37.5% vs 15.8%, p = 0.021); however, there was no significant difference in overall (p = 0.2) or progression-free (p = 0.4) survival. Supratentorial NF2 mutant meningiomas are associated with more aggressive clinical and genomic features as compared with their infratentorial counterparts. Although infratentorial tumors have higher rates of subtotal resection, there is no associated difference in survival or recurrence. These findings help to better inform surgical decision-making in the management of NF2 mutant meningiomas based on location, and may guide postoperative management of these tumors.

Primer caso de displasia tanatofórica tipo 1 en los andes peruanos con variante patogénica en el gen FGFR3

Thanatophoric dysplasia type 1 is a form of lethal skeletal dysplasia, characterized by axial-appendicular skeletal disproportions as well as short stature, frontal bossing, cloverleaf skull, narrow chest, femoral bowing, and micromelia. These phenotypic characteristics are the result of pathogenic variants in the fibroblast growth factor receptor 3 (FGFR-3) gene, located on chromosome 4p16.3 For its study, obstetric ultrasound, physical examination and radiographic findings are important. However, the diagnosis must be confirmed by genetic study in order to discover new variants or associations, as well as to reveal its actual casuistry in a certain region.